Caveolin 3 Explained

Caveolin-3 is a protein that in humans is encoded by the CAV3 gene.^{[1] [2] [3]} Alternative splicing has been identified for this locus, with inclusion or exclusion of a differentially spliced intron. In addition, transcripts utilize multiple polyA sites and contain two potential translation initiation sites.

Function

This gene encodes a caveolin family member, which functions as a component of the caveolae plasma membranes found in most cell types. Caveolin proteins are proposed to be scaffolding proteins for organizing and concentrating certain caveolin-interacting molecules.

Clinical significance

Mutations identified in this gene lead to interference with protein oligomerization or intra-cellular routing, disrupting caveolae formation and resulting in Limb-Girdle muscular dystrophy type-1C (LGMD-1C), HyperCKemia, distal myopathy or rippling muscle disease (RMD). Other mutations in Caveolin causes Long QT Syndrome or familial hypertrophic cardiomyopathy, although the role of Cav3 in Long QT syndrome has recently been disputed.^[4]

Interactions

Caveolin 3 has been shown to interact with a range of different proteins, including, but not limited to:

• DAG1,^[5]
• DYSF,^[6]
• EGFR,^[7] and
• RYR1.^[8]

Structure

Using transmission electron microscopy and single particle analysis methods, it has been shown that nine Caveolin-3 monomers assemble to form a complex that is toroidal in shape, ~16.5 nm in diameter and ~5.5 nm in height.^[9]

Cardiac physiology

Caveolin-3 is one of three isoforms of the protein caveolin.^[10] Caveolin-3 is concentrated in the caveolae of myocytes, and modulates numerous metabolic processes including: nitric oxide synthesis, cholesterol metabolism, and cardiac myocytes contraction.^{[11] [12]} There are many proteins that associate with caveolin-3, including ion channels and exchangers.^{[13] [14] [15] [16] [17] [18] [19]}

Associations with ion channels

ATP-dependent potassium channels

In cardiac myocytes, caveolin-3 negatively regulates ATP-dependent potassium channels (K_ATP) localized in caveolae. K_ATP channel opening decreases significantly when interacting with caveolin-3; other isoforms of caveolin do not show this type of effect on K_ATP channels. The amount of K_ATP activation during times of biological stress influences the amount of cellular damage that will occur, thus regulation of caveolin-3 expression during these times influences the amount of cellular damage.

Sodium-calcium exchanger

Caveolin-3 associates with the cardiac sodium-calcium exchanger (NCX) in caveolae of cardiac myocytes.^[20] This association occurs predominately in areas proximate to the peripheral membrane of cardiac myocytes. Interactions between caveolin-3 and cardiac NCX influence NCX-regulation of cellular signaling factors and excitation of cardiac myocytes.

L-Type calcium channel

Caveolin-3 influences the opening of L-Type calcium channels (LTCC) which play a role in cardiac myocyte contraction. Disruption of interactions between caveolin-3 and its associated binding proteins has been shown to affect LTCC. Specifically, disruption of caveolin-3 decreases the basal and b₂-adrenergic-stimulated opening probabilities of LTCC. This occurs by changing the PKA-mediated phosphorylation of caveolin-3-associated binding proteins, causing negative down-stream effects on LTCC activity.

Implications in disease

Alterations in caveolin-3 expression have been implicated in the altered expression and regulation of numerous signaling molecules involved in cardiomyopathies. Disruption of caveolin-3 disturbs the structure of cardiac caveolae and blocks atrial natriuretic peptide (ANP) expression, a cardiac-related hormone involved in many functions including maintaining cellular homeostasis.^[21] Normal caveolin-3 expression under conditions of stress increases cardiac cellular levels of ANP, maintaining cardiac homeostasis. Mutations have been identified in the caveolin-3 gene that result in cardiomyopathies. Several of these mutations influence caveolin-3 function by reducing the expression of its cell-surface domains. Mutations resulting in loss-of-function of caveolin-3 cause cardiac myocyte hypertrophy, dilation of the heart, and depression of fractional shortening. Knockout of caveolin-3 genes are sufficient to induce these manifestations. Similarly, dominant-negative genotypes for caveolin-3 increase cardiac hypertrophy, whereas increased expression of caveolin-3 inhibits the ability of the heart to hypertrophy, implicating caveolin-3 as a negative regulator of cardiac hypertrophy. Overexpression of caveolin-3 leads to the development of cardiomyopathy, resulting in degeneration of cardiac tissue and manifesting pathologies due to the associated degeneration.

Further reading

• Figarella-Branger D, Pouget J, Bernard R, Krahn M, Fernandez C, Lévy N, Pellissier JF . Limb-girdle muscular dystrophy in a 71-year-old woman with an R27Q mutation in the CAV3 gene . Neurology . 61 . 4 . 562–4 . 2004 . 12939441 . 10.1212/01.wnl.0000076486.57572.5c . 40129179 .
• Woodman SE, Sotgia F, Galbiati F, Minetti C, Lisanti MP . Caveolinopathies: mutations in caveolin-3 cause four distinct autosomal dominant muscle diseases . Neurology . 62 . 4 . 538–43 . 2005 . 14981167 . 10.1212/wnl.62.4.538 .
• Li S, Okamoto T, Chun M, Sargiacomo M, Casanova JE, Hansen SH, Nishimoto I, Lisanti MP . Evidence for a regulated interaction between heterotrimeric G proteins and caveolin . J. Biol. Chem. . 270 . 26 . 15693–701 . 1995 . 7797570 . 10.1074/jbc.270.26.15693 . free .
• Tang Z, Scherer PE, Okamoto T, Song K, Chu C, Kohtz DS, Nishimoto I, Lodish HF, Lisanti MP . Molecular cloning of caveolin-3, a novel member of the caveolin gene family expressed predominantly in muscle . J. Biol. Chem. . 271 . 4 . 2255–61 . 1996 . 8567687 . 10.1074/jbc.271.4.2255 . free .
• Scherer PE, Lisanti MP . Association of phosphofructokinase-M with caveolin-3 in differentiated skeletal myotubes. Dynamic regulation by extracellular glucose and intracellular metabolites . J. Biol. Chem. . 272 . 33 . 20698–705 . 1997 . 9252390 . 10.1074/jbc.272.33.20698 . free.
• Venema VJ, Ju H, Zou R, Venema RC . Interaction of neuronal nitric-oxide synthase with caveolin-3 in skeletal muscle. Identification of a novel caveolin scaffolding/inhibitory domain . J. Biol. Chem. . 272 . 45 . 28187–90 . 1997 . 9353265 . 10.1074/jbc.272.45.28187 . free .
• Couet J, Sargiacomo M, Lisanti MP . Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities . J. Biol. Chem. . 272 . 48 . 30429–38 . 1997 . 9374534 . 10.1074/jbc.272.48.30429 . free .
• Biederer C, Ries S, Drobnik W, Schmitz G . Molecular cloning of human caveolin 3 . Biochim. Biophys. Acta . 1406 . 1 . 5–9 . 1998 . 9545514 . 10.1016/S0925-4439(97)00095-1 .
• Yamamoto M, Toya Y, Schwencke C, Lisanti MP, Myers MG, Ishikawa Y . Caveolin is an activator of insulin receptor signaling . J. Biol. Chem. . 273 . 41 . 26962–8 . 1998 . 9756945 . 10.1074/jbc.273.41.26962 . free .
• Sotgia F, Minetti C, Lisanti MP . Localization of the human caveolin-3 gene to the D3S18/D3S4163/D3S4539 locus (3p25), in close proximity to the human oxytocin receptor gene. Identification of the caveolin-3 gene as a candidate for deletion in 3p-syndrome . FEBS Lett. . 452 . 3 . 177–80 . 1999 . 10386585 . 10.1016/S0014-5793(99)00658-4 . 44686134 . free .
• Carbone I, Bruno C, Sotgia F, Bado M, Broda P, Masetti E, Panella A, Zara F, Bricarelli FD, Cordone G, Lisanti MP, Minetti C . Mutation in the CAV3 gene causes partial caveolin-3 deficiency and hyperCKemia . Neurology . 54 . 6 . 1373–6 . 2000 . 10746614 . 10.1212/wnl.54.6.1373 . 74588429 .
• Biederer CH, Ries SJ, Moser M, Florio M, Israel MA, McCormick F, Buettner R . The basic helix-loop-helix transcription factors myogenin and Id2 mediate specific induction of caveolin-3 gene expression during embryonic development . J. Biol. Chem. . 275 . 34 . 26245–51 . 2000 . 10835421 . 10.1074/jbc.M001430200 . free .
• Sotgia F, Lee JK, Das K, Bedford M, Petrucci TC, Macioce P, Sargiacomo M, Bricarelli FD, Minetti C, Sudol M, Lisanti MP . Caveolin-3 directly interacts with the C-terminal tail of beta -dystroglycan. Identification of a central WW-like domain within caveolin family members . J. Biol. Chem. . 275 . 48 . 38048–58 . 2001 . 10988290 . 10.1074/jbc.M005321200 . free .
• Herrmann R, Straub V, Blank M, Kutzick C, Franke N, Jacob EN, Lenard HG, Kröger S, Voit T . Dissociation of the dystroglycan complex in caveolin-3-deficient limb girdle muscular dystrophy . Hum. Mol. Genet. . 9 . 15 . 2335–40 . 2001 . 11001938 . 10.1093/oxfordjournals.hmg.a018926 . free .
• Hagiwara Y, Sasaoka T, Araishi K, Imamura M, Yorifuji H, Nonaka I, Ozawa E, Kikuchi T . Caveolin-3 deficiency causes muscle degeneration in mice . Hum. Mol. Genet. . 9 . 20 . 3047–54 . 2001 . 11115849 . 10.1093/hmg/9.20.3047 . free .
• de Paula F, Vainzof M, Bernardino AL, McNally E, Kunkel LM, Zatz M . Mutations in the caveolin-3 gene: When are they pathogenic? . Am. J. Med. Genet. . 99 . 4 . 303–7 . 2001 . 11251997 . 10.1002/1096-8628(2001)9999:9999<::AID-AJMG1168>3.0.CO;2-O .
• Betz RC, Schoser BG, Kasper D, Ricker K, Ramírez A, Stein V, Torbergsen T, Lee YA, Nöthen MM, Wienker TF, Malin JP, Propping P, Reis A, Mortier W, Jentsch TJ, Vorgerd M, Kubisch C . Mutations in CAV3 cause mechanical hyperirritability of skeletal muscle in rippling muscle disease . Nat. Genet. . 28 . 3 . 218–9 . 2001 . 11431690 . 10.1038/90050 . 35194603 .
• Matsuda C, Hayashi YK, Ogawa M, Aoki M, Murayama K, Nishino I, Nonaka I, Arahata K, Brown RH . The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle . Hum. Mol. Genet. . 10 . 17 . 1761–6 . 2002 . 11532985 . 10.1093/hmg/10.17.1761 . free .

Notes and References

1. McNally EM, de Sá Moreira E, Duggan DJ, Bönnemann CG, Lisanti MP, Lidov HG, Vainzof M, Passos-Bueno MR, Hoffman EP, Zatz M, Kunkel LM . Caveolin-3 in muscular dystrophy . Hum Mol Genet . 7 . 5 . 871–7 . August 1998 . 9536092 . 10.1093/hmg/7.5.871 . free .
2. Minetti C, Sotgia F, Bruno C, Scartezzini P, Broda P, Bado M, Masetti E, Mazzocco M, Egeo A, Donati MA, Volonte D, Galbiati F, Cordone G, Bricarelli FD, Lisanti MP, Zara F . Mutations in the caveolin-3 gene cause autosomal dominant limb-girdle muscular dystrophy . Nat Genet . 18 . 4 . 365–8 . April 1998 . 9537420 . 10.1038/ng0498-365 . 35061895 .
3. Web site: Entrez Gene: CAV3 caveolin 3.
4. Hedley PL, Kanters JK, Dembic M, Jespersen T, Skibsbye L, Aidt FH, Eschen O, Graff C, Behr ER, Schlamowitz S, Corfield V, McKenna WJ, Christiansen M . The Role of CAV3 in Long-QT Syndrome: Clinical and Functional Assessment of a Caveolin-3/Kv11.1 Double Heterozygote Versus Caveolin-3 Single Heterozygote . Circ Cardiovasc Genet . 6 . 5 . 452–61 . 2013 . 24021552 . 10.1161/CIRCGENETICS.113.000137 . free .
5. Sotgia F, Lee JK, Das K, Bedford M, Petrucci TC, Macioce P, Sargiacomo M, Bricarelli FD, Minetti C, Sudol M, Lisanti MP . Caveolin-3 directly interacts with the C-terminal tail of beta -dystroglycan. Identification of a central WW-like domain within caveolin family members . J. Biol. Chem. . 275 . 48 . 38048–58 . December 2000 . 10988290 . 10.1074/jbc.M005321200 . free .
6. Matsuda C, Hayashi YK, Ogawa M, Aoki M, Murayama K, Nishino I, Nonaka I, Arahata K, Brown RH . The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle . Hum. Mol. Genet. . 10 . 17 . 1761–6 . August 2001 . 11532985 . 10.1093/hmg/10.17.1761 . free .
7. Couet J, Sargiacomo M, Lisanti MP . Interaction of a receptor tyrosine kinase, EGF-R, with caveolins. Caveolin binding negatively regulates tyrosine and serine/threonine kinase activities . J. Biol. Chem. . 272 . 48 . 30429–38 . November 1997 . 9374534 . 10.1074/jbc.272.48.30429 . free .
8. Whiteley G, Collins RF, Kitmitto A . Characterization of the molecular architecture of human caveolin-3 and interaction with the skeletal muscle ryanodine receptor . J. Biol. Chem. . 287 . 48 . 40302–16 . November 2012 . 23071107 . 3504746 . 10.1074/jbc.M112.377085 . free .
9. Whiteley G, Collins RF, Kitmitto A . Characterization of the molecular architecture of human caveolin-3 and interaction with the skeletal muscle ryanodine receptor. . The Journal of Biological Chemistry . 287 . 48 . 40302–16 . Nov 23, 2012 . 23071107 . 3504746 . 10.1074/jbc.M112.377085 . free .
10. Bossuyt J, Taylor BE, James-Kracke M, Hale CC . Evidence for cardiac sodium-calcium exchanger association with caveolin-3 . FEBS Lett. . 511 . 1–3 . 113–7 . 2002 . 11821059 . 10.1016/S0014-5793(01)03323-3 . 19419069 . free .
11. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, Minetti C . Caveolinopathies: from the biology of caveolin-3 to human diseases . Eur. J. Hum. Genet. . 18 . 2 . 137–45 . 2010 . 19584897 . 2987183 . 10.1038/ejhg.2009.103 .
12. Gratton JP, Bernatchez P, Sessa WC . Caveolae and caveolins in the cardiovascular system . Circ. Res. . 94 . 11 . 1408–17 . 2004 . 15192036 . 10.1161/01.RES.0000129178.56294.17 . free .
13. Bryant S, Kimura TE, Kong CH, Watson JJ, Chase A, Suleiman MS, James AF, Orchard CH . Stimulation of ICa by basal PKA activity is facilitated by caveolin-3 in cardiac ventricular myocytes . J. Mol. Cell. Cardiol. . 68 . 47–55 . 2014 . 100 . 24412535 . 3980375 . 10.1016/j.yjmcc.2013.12.026 .
14. Garg V, Sun W, Hu K . Caveolin-3 negatively regulates recombinant cardiac K(ATP) channels . Biochem. Biophys. Res. Commun. . 385 . 3 . 472–7 . 2009 . 19481058 . 10.1016/j.bbrc.2009.05.100 .
15. Aravamudan B, Volonte D, Ramani R, Gursoy E, Lisanti MP, London B, Galbiati F . Transgenic overexpression of caveolin-3 in the heart induces a cardiomyopathic phenotype . Hum. Mol. Genet. . 12 . 21 . 2777–88 . 2003 . 12966035 . 10.1093/hmg/ddg313 . free .
16. Hayashi T, Arimura T, Ueda K, Shibata H, Hohda S, Takahashi M, Hori H, Koga Y, Oka N, Imaizumi T, Yasunami M, Kimura A . Identification and functional analysis of a caveolin-3 mutation associated with familial hypertrophic cardiomyopathy . Biochem. Biophys. Res. Commun. . 313 . 1 . 178–84 . January 2004 . 14672715 . 10.1016/j.bbrc.2003.11.101 .
17. Horikawa YT, Panneerselvam M, Kawaraguchi Y, Tsutsumi YM, Ali SS, Balijepalli RC, Murray F, Head BP, Niesman IR, Rieg T, Vallon V, Insel PA, Patel HH, Roth DM . Cardiac-specific overexpression of caveolin-3 attenuates cardiac hypertrophy and increases natriuretic peptide expression and signaling . J. Am. Coll. Cardiol. . 57 . 22 . 2273–83 . 2011 . 21616289 . 3236642 . 10.1016/j.jacc.2010.12.032 .
18. Koga A, Oka N, Kikuchi T, Miyazaki H, Kato S, Imaizumi T . Adenovirus-mediated overexpression of caveolin-3 inhibits rat cardiomyocyte hypertrophy . Hypertension . 42 . 2 . 213–9 . 2003 . 12847114 . 10.1161/01.HYP.0000082926.08268.5D . free .
19. Woodman SE, Park DS, Cohen AW, Cheung MW, Chandra M, Shirani J, Tang B, Jelicks LA, Kitsis RN, Christ GJ, Factor SM, Tanowitz HB, Lisanti MP . Caveolin-3 knock-out mice develop a progressive cardiomyopathy and show hyperactivation of the p42/44 MAPK cascade . J. Biol. Chem. . 277 . 41 . 38988–97 . 2002 . 12138167 . 10.1074/jbc.M205511200 . free .
20. Lin E, Hung VH, Kashihara H, Dan P, Tibbits GF . Distribution patterns of the Na+-Ca2+ exchanger and caveolin-3 in developing rabbit cardiomyocytes . Cell Calcium . 45 . 4 . 369–83 . 2009 . 19250668 . 10.1016/j.ceca.2009.01.001 .
21. Nakajima K, Onishi K, Dohi K, Tanabe M, Kurita T, Yamanaka T, Ito M, Isaka N, Nobori T, Nakano T . Effects of human atrial natriuretic peptide on cardiac function and hemodynamics in patients with high plasma BNP levels . Int. J. Cardiol. . 104 . 3 . 332–7 . 2005 . 16186065 . 10.1016/j.ijcard.2004.12.020 .